The goals of Project 2, Clinical Investigations, are to use the clinical material from Project 1 and the tools from Project 3 to provide data on: 1) the dose response relationships of normal tissues to include partial volume effects; 2) the effects on local tumor control of dose heterogeneity in the tumor; 3) the sites and diseases where the benefits of proton radiation therapy are likely to be greatest; 4) the dose localization characteristics of conformal x-ray and proton treatments; and 5) the importance in tumor localization and treatment follow-up of multi- modality imaging studies. The investigations of the dose response of normal tissues will include studies on: tumor vasculature in choroidal or ciliary body melanomas; clinically evident damage to cranial nerves and nuclei; incidence, severity and dose relationship for temporal lobe; neuropsychological effects of irradiation to the normal brain; effects of irradiation of the pituitary hypothalamic axis; and, effects of irradiation on hearing loss. We will continue oui studies of the radiation tolerance of the optic nerves and optic chiasm, brain stem and spinal cord in patients treated for tumors of the skull base and cervical spine and of the spinal nerve roots and peripheral nerves in patients treated for tumors of the cervical, dorsal, and lumbar spine. We will investigate the correlation between tumor control probability and dose heterogeneity in those patients with tumors abutting the brain stem, optic nerves and/or chiasm where the tolerance of these tissues limits the tumor dose, resulting in regions of the target volume receiving dose less than that prescribed. We will continue our comparative treatment planning studies to determine additional disease sites likely to benefit significantly from proton radiation therapy. The comparisons will be made against the very best x- ray beam conformal therapy treatment plans so that we can gain a realistic assessment of the advantages of proton dose distributions. We will expand the use of multi-modality imaging studies to define the target volumes in patients treated in the astrocytoma protocol, follow tumor regression, and monitor normal tissue status following high dose therapy.